Enantiospecific total synthesis of the squalene synthase inhibitors (–)-CJ-13,982 and its enantiomer from a common intermediate

Abstract

The total syntheses of both the natural and unnatural enantiomers of the alkyl citrate natural product CJ-13,982 (1) from the common d-ribose-derived acid 6 are described.

Synthesis of Alkyl Citrates (−)-CJ-13,981, (−)-CJ-13,982, and (−)-L-731,120 via a Cyclobutene Diester

“…We have reported the synthesis of natural (−)-CJ-13,982 ( 1 ) which utilized an Ireland–Claisen rearrangement as the key step to introduce the two asymmetric centers with some degree of stereocontrol but in low overall yield (Figure ). The synthesis of the proposed stereoisomer of L-731,120 ( 3 ) has not been reported. These approaches to simple alkyl citrates are lengthy due multiple functional group transformations.…”

“…Cross metathesis (CM) with undecene followed by hydrogenation afforded (−)-CJ-13,982 trimethyl ester 18 . This compound compared well with that reported by us and by Barrett (except for the sign of rotation) …”

“…Cyclobutenediesters can be readily accessed via the formal [2 + 2]-cycloaddition of ketene acetals with acetylenic diesters. 14 Dimethyl acetylenedicarboxylate (DMAD) (10) reacts with alkyl 14,15 and silyl ketene acetals in the absence of Lewis acid and solvent 11,12 to produce cyclobutene diesters. In our hands, the cyclobutenes produced from TMS ketene acetals proved too labile, so we elected to utilize the TBS ketene acetal.…”

In vitro studies of maleidride-forming enzymes

“…In the cases of other known citratederived metabolites (and in primary metabolism) the 3S conguration is also observed, but in the known cases of squalestatin S1 9, viridiofungin 8 and CJ-13,981 7, for example, the CS products are 3S,4S. 7,40,41 Differences in conguration at the 4-position must be controlled by the geometry of the enoyl CoA intermediate, and in-turn this may be related to the ability of the BfL2 CS to react 2,3-unsaturated substrates. Detailed structural work will be required to probe this question further.…”

“…This step is closely related to the primary metabolism enzyme 2-methylcitrate dehydratase (2MCDH). Again the stereoselectivity of this step by the primary metabolism 2-methylcitrate dehydratase has been debated, but Reddick's results 41 conclusively show that the enzyme takes 3 S *,4 R * isomer to give Z -methyl aconitate – i.e . anti dehydration.…”